Anne Griffiths

University of Toronto, Toronto, Ontario, Canada

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Publications (111)665.35 Total impact

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    ABSTRACT: Background: While family history provides important information on risk of developing Inflammatory Bowel Disease (IBD), genetic profiling of first degree relatives (FDR) of Crohn's Disease (CD) - affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. Methods: N=976 Caucasian, healthy, non-related FDR; n=4997 independent CD and n=5000 healthy controls (HC); were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms (SNPs) was performed using the Illumina Immunochip. Risk allele frequency (RAF) differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores (GRS) were calculated and compared between HC, FDR and CD cohorts. Results: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 [95%CI 0.53 - 0.72], p = 9.90 x 10(-19). There was a significant increase in CD-GRS (mean) comparing HC, FDR and CD cohorts: 0.0244, 0.0250 and 0.0257 respectively (p < 1 x 10(-7) for each comparison). There was no significant difference in the IBD-GRS between HC and FDR cohorts (p=0.81); however IBD-GRS was significantly higher in CD compared with FDR and HC cohorts (p < 10(-10) for each comparison). Conclusion: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
    Journal of Crohn s and Colitis 10/2015; DOI:10.1093/ecco-jcc/jjv197 · 6.23 Impact Factor
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    ABSTRACT: The Genetics, Environmental, Microbial Project is a multicenter study assessing etiological factors in Crohn's disease by studying healthy first-degree relatives (FDRs) of individuals affected by Crohn's disease. We aimed to evaluate the contribution of genetic, microbial, and environmental factors to the determination of intestinal permeability in healthy FDRs. IP was assessed using the lactulose-mannitol ratio (LacMan ratio). FDRs were genotyped for 167 inflammatory bowel disease-associated single nucleotide polymorphisms. Taxonomic profile of the fecal microbiota was determined by Illumina MiSeq pyrosequencing of 16S ribosomal RNA. The associations of LacMan ratio with demographic factors, inflammatory bowel disease-associated single nucleotide polymorphisms and the fecal microbiota were assessed. One hundred ninety-six white FDRs were included. Eleven percent of FDRs had an elevated LacMan ratio (≥0.03). A multivariate analysis demonstrated that younger subjects and nonsmokers had higher LacMan ratios, P = 3.62 × 10 and P = 0.03, respectively. The LacMan ratio was not significantly heritable, H2r, 0.13, P = 0.13. There was no association between any of the 167 inflammatory bowel disease-associated risk variants and LacMan ratio nor was there a correlation between fecal microbial composition and the LacMan ratio. We did not find LacMan ratio to be significantly heritable suggesting that the contribution of genetic factors to the determination of intestinal permeability in healthy FDRs is modest. Environmental factors, such as smoking, are likely more important determinants. The effect of age on intestinal barrier function has been underappreciated.
    Inflammatory Bowel Diseases 03/2015; 21(4). DOI:10.1097/MIB.0000000000000323 · 4.46 Impact Factor
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    ABSTRACT: Background In the treatment of Crohn's disease (CD), mucosal healing has become a major goal, with the hope of avoiding intestinal damage from chronic inflammation. Magnetic resonance enterography (MRE) has emerged as a non-invasive means of monitoring inflammation and damage.AimsAs part of the development of MRE-based multi-item measures of inflammation and damage for paediatric studies, we carried out a systematic review and meta-analysis to identify MRE variables used to describe these two distinct concepts.Methods2501 studies of MRI and CD were identified. Studies written in any language reporting individual MRE signs for patients diagnosed with CD were included. Two-hundred-and-forty-four studies were fully reviewed and 62 were included (inflammation, n = 51; damage, n = 24). Sensitivity, specificity and associated confidence intervals were calculated, and hierarchical summary ROC curves were constructed for each MRE sign.ResultsA total of 22 MRE signs were used to reflect inflammation, and 9 to reflect damage. Diagnostic accuracy of MRE signs of inflammation and damage was heterogeneous; however, wall enhancement, mucosal lesions and wall T2 hyperintensity were the most consistently useful for inflammation (most sensitivities >80% and specificities >90%), and detection of abscess and fistula were most consistently useful for damage (most sensitivities >90%, specificities >95%).Conclusions Identifying the best MRE variables to reflect inflammation and damage will maximise the utility of this rapidly emerging technique and is the first stage of constructing MRE-based indices for evaluating inflammation and intestinal damage.
    Alimentary Pharmacology & Therapeutics 11/2014; 41(2). DOI:10.1111/apt.13024 · 5.73 Impact Factor
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    ABSTRACT: Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%-18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%-9.5%), whereas 4.5% (95% CI 2.8%-7.2%) of patients required discontinuation. Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.
    Inflammatory Bowel Diseases 11/2013; 20(1). DOI:10.1097/01.MIB.0000436953.88522.3e · 4.46 Impact Factor
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    ABSTRACT: To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every (q) 8 weeks through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Infliximab pharmacokinetics was not influenced by age (6-11 yr versus 12-17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 μg/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 μg/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 μg/mL) versus q12w (0.8 μg/mL) and with infliximab 10 mg/kg (2.9 μg/mL) versus 5 mg/kg (1.1 μg/mL) among patients who are regimen adjusted. Infliximab pharmacokinetics/exposure-response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.
    Inflammatory Bowel Diseases 11/2013; 19(13). DOI:10.1097/01.MIB.0000435438.84365.f7 · 4.46 Impact Factor

  • 16th International Congress of Mucosal Immunology, Vancouver, British Columbia, Canada; 07/2013

  • Gastrointestinal Division Research Day, Toronto, Ontario, Canada; 06/2013
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    ABSTRACT: It has been suggested that IBD involves altered interactions between genetically determined immune responses to environmental challenges such as gut bacteria. In order to determine if composition of gut microbiotas are related to genes associated with risk for developing CD, we assessed the microbiome in a cohort of 578 FDR of CD patients enriched for the genetic variations associated with an increased risk of CD. The subjects were selected from the GEM Project cohort on the basis of their ethnicity. Bacterial DNA was extracted from stool samples using QIAamp DNA Stool Mini Kit and V1-V3 hypervariable regions of bacterial 16S rRNA genes were sequenced using 454 pyrosequencing. These sequences were treated using the QIIME pipeline and USEARCH. The operational taxonomic units (OTUs) obtained were assigned to taxonomic classification using the RDP 2.2 and Greengenes (Feb 2011) core sequences. We analyzed the relationship of OTU composition with 30 of the most common disease-associated polymorphisms (SNPs) genotyped using Sequenom Gold iPlex or TaqMan platforms. The data were rarefied 50 times at equal sampling depth and statistical tests were done using ANOVA with p-value False Discovery Rate corrected for multiple comparisons (36x104). A total of 3,377,987 reads were obtained with an average of 4,286 ± 72 reads per subject. Overall, the dominant genera in these samples were Bacteroidetes, Faecalibacterium and Roseburia (23.9%±0.9, 18.0% ± 0.6, 12.3% ± 0.4 of total OTUs, respectively). Differences in the microbiome makeup were associated with two interleukin 23 receptor (IL23R) SNPs, rs11209026 and rs11465804. Heterozygotes for rs11209026 (reduced risk for CD) were associated with higher proportions of Bacteroides, Odoribacter and lower proportions of Clostridium, Faecalibacterium, Lachnospira, and Subdoligranulum (with a range of p=10-8 to 0.02). Similar results were obtained with rs11465804. In addition, risk alleles of NOD2, rs2066844 and rs2066847, were associated with higher proportions of Gammaproteobacteria (p<0.04). The immunity-related GTPase family M (IRGM) rs13361189 risk allele was associated with a lower proportion of Bacteroidia and an increase of Erysipelotrichi (p<0.03). The toll-like receptor 4 (TLR4) risk allele rs4986790 was associated with a higher proportion of Streptococceace (p<0.05). These results indicate differences exist in the intestinal microbiota which are associated with SNPs in IL23R, IRGM, NOD2 and TLR4. These results from healthy FDR differ from prior studies of changes in microbiota in patients with CD, potentially indicating that genetic associations with microbiota may be difficult to evaluate in the context of established inflammation. Our results represent the largest study defining the association between differences in the microbiota and host CD risk alleles in asymptomatic individuals.
    Digestive Diseases Week 2013, Orlando, Florida, United States; 05/2013

  • Canadian Digestive Diseases Week 2013; 03/2013
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    ABSTRACT: Objectives: Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA. Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy). Results: Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used. Conclusions: Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.
    Journal of pediatric gastroenterology and nutrition 07/2012; 56(1). DOI:10.1097/MPG.0b013e31826ac41a · 2.63 Impact Factor
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    ABSTRACT: The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohn's disease (CD). We studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores >30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or <40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or <40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or <40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety. A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected. Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.
    Gastroenterology 05/2012; 143(2):365-74.e2. DOI:10.1053/j.gastro.2012.04.046 · 16.72 Impact Factor
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    ABSTRACT: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid-related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD. Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined. BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD ≤ 30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD ≤ 30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD ≤ 30 days of diagnosis. Two-thirds (77/119) of patients received BUD for ≤ 6 months. BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD.
    Journal of pediatric gastroenterology and nutrition 01/2012; 55(2):200-4. DOI:10.1097/MPG.0b013e31824a09c2 · 2.63 Impact Factor
  • Article: Reply.
    Anne Tsampalieros · Anne Griffiths · Nick Barrowman · David R Mack ·

    The Journal of pediatrics 01/2012; 160(3):530-1. DOI:10.1016/j.jpeds.2011.11.048 · 3.79 Impact Factor
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    ABSTRACT: We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC). Patients (6-17 years old) who had active UC (Mayo scores of 6-12; endoscopic subscores ≥ 2) and had not responded to or tolerated conventional treatment were given 5 mg/kg infliximab at weeks 0, 2, and 6. The primary end point was response at week 8 (decreases in Mayo scores ≥ 30% and ≥ 3 points and decreases in rectal bleeding subscores of ≥ 1 or an absolute subscore of ≤ 1). At week 8, only responders were randomly assigned to groups given infliximab every 8 or 12 weeks (q8w or q12w) and followed through week 54. Maintenance end points included pediatric UC activity index scores <10 points, defined as remission. At week 8, infliximab induced a response in 73.3% of patients (44 of 60) (95% confidence interval, 62.1%-84.5%; a positive result was defined by 95% confidence interval lower limit >40%). Among responders, twice as many were in remission at week 54 after q8w (8 of 21, 38.1%) than q12w (4 of 22, 18.2%; P = .146) therapy. Assuming the q8w remission rate for responders, the overall remission rate at week 54 would be 28.6%. Serious adverse events and infusion reactions occurred in similar proportions in the q8w and q12w groups. No deaths, malignancies, opportunistic infections, tuberculosis, or delayed hypersensitivity reactions were reported. Infliximab was safe and effective, inducing a response at week 8 in 73.3% of pediatric patients with moderate to severely active UC who did not respond to conventional therapy. The overall remission rate at week 54 for all enrolled patients was 28.6%, assuming the more effective q8w remission rate.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2011; 10(4):391-9.e1. DOI:10.1016/j.cgh.2011.11.026 · 7.90 Impact Factor
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    ABSTRACT: Crohn's disease and ulcerative colitis are complex disorders with some shared and many unique predisposing genes. Accurate phenotype classification is essential in determining the utility of genotype-phenotype correlation. The Montreal Classification of IBD has several weaknesses with respect to classification of children. The dynamic features of pediatric disease phenotype (change in disease location and behavior over time, growth failure) are not sufficiently captured by the current Montreal Classification. Focusing on facilitating research in pediatric inflammatory bowel disease (IBD), and creating uniform standards for defining IBD phenotypes, an international group of pediatric IBD experts met in Paris, France to develop evidence-based consensus recommendations for a pediatric modification of the Montreal criteria. Important modifications developed include classifying age at diagnosis as A1a (0 to <10 years), A1b (10 to <17 years), A2 (17 to 40 years), and A3 (>40 years), distinguishing disease above the distal ileum as L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum), allowing both stenosing and penetrating disease to be classified in the same patient (B2B3), denoting the presence of growth failure in the patient at any time as G(1) versus G(0) (never growth failure), adding E4 to denote extent of ulcerative colitis that is proximal to the hepatic flexure, and denoting ever severe ulcerative colitis during disease course by S1. These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists.
    Inflammatory Bowel Diseases 06/2011; 17(6):1314-21. DOI:10.1002/ibd.21493 · 4.46 Impact Factor
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    ABSTRACT: Assess long-term effects of maintenance infliximab therapy in children with moderately-to-severely active Crohn's disease. One hundred twelve patients with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6 in the REACH study. Patients considered responders at week 10 were randomized to infliximab 5 mg/kg every 8 (q8w) or 12 (q12w) weeks. Patients who completed treatment through week 46, and who the investigator believed would benefit from continued treatment, could enter the open-label extension (OLE) and receive up to three additional years of infliximab. No hypothesis testing was performed., identifier: NCT0020767. Sixty children entered the OLE: 33, 12, and 15 patients were receiving infliximab 5 mg/kg q8w, 5 mg/kg q12w, and 10 mg/kg q8w, respectively, at extension entry. Patients receiving infliximab for up to 3 years during the OLE maintained clinical benefit, with approximately 80% of patients consistently having no to mild disease activity per the physician's global assessment and very good to fair health in the past 2 weeks per the patient and parent/guardian global assessments. Patients with ≥1-year delay in bone age at baseline trended toward improvement in height during the OLE. Respiratory system disorders, most commonly upper respiratory infections, were the most prevalent adverse events reported; six (10%) patients had serious infections. Among children with moderately-to-severely active Crohn's disease who received infliximab for 46 weeks in REACH and then for up to 3 additional years in the REACH OLE, infliximab was effective in maintaining clinical benefit and was generally well-tolerated.
    Current Medical Research and Opinion 03/2011; 27(3):651-62. DOI:10.1185/03007995.2010.547575 · 2.65 Impact Factor
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    ABSTRACT: Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC. Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year. Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.
    The American Journal of Gastroenterology 01/2011; 106(5):981-7. DOI:10.1038/ajg.2010.493 · 10.76 Impact Factor
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    ABSTRACT: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
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    Nature Genetics 01/2011; · 29.35 Impact Factor
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    ABSTRACT: To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. This was a prospective multicentre cohort study. Stool samples from 101 children (13.3 + or - 3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72 + or - 12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician's global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 microg/g (2297-8808); lactoferrin 212 microg/g (114-328); M2-pyruvate kinase (M2-PK) 363 U/g (119-3104); and S100A12 469 microg/g (193-1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearman's rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.
    Gut 09/2010; 59(9):1207-12. DOI:10.1136/gut.2010.211755 · 14.66 Impact Factor

Publication Stats

6k Citations
665.35 Total Impact Points


  • 1997-2014
    • University of Toronto
      • • Hospital for Sick Children
      • • Division of Gastroenterology
      • • Department of Paediatrics
      Toronto, Ontario, Canada
  • 2003-2013
    • SickKids
      • Division of Gastroenterology, Hepatology and Nutrition
      Toronto, Ontario, Canada
  • 2009
    • The Children's Hospital of Philadelphia
      • Center for Applied Genomics
      Philadelphia, PA, United States
  • 2008
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom